Pancreas has endocrine glands (endocrine cells) and exocrine glands (exocrine cells), and is an organ playing an important role in the both secretory cells. Exocrine cells mainly play a role of secreting digestive enzymes such as pancreatic lipase, trypsin, elastase, pancreatic amylase and the like.
Endocrine cells play a role of secreting pancreatic hormone, and it is known that glucagon is secreted from pancreatic α cells, insulin is secreted from pancreatic β cells, somatostatin is secreted from pancreatic δ cells, and pancreatic polypeptide (PP) is secreted from PP cells. In recent years, it has been reported that ghrelin, which is a stomach-secreted hormone is also secreted from endocrine cells of the pancreas.
Insulin plays an important role of promoting utilization of glucose, protein synthesis, and formation and storage of neutral fats, lowering blood glucose level, and maintaining blood glucose at a correct concentration. Glucagon plays an important role, along with insulin, in a sugar metabolism regulatory mechanism, as a hyperglycemic hormone via hepatic glycogenolysis, gluconeogenesis action and the like. Somatostatin expresses an action by binding to a somatostatin receptor, and suppresses secretion of various hormones such as glucagon, insulin and the like in the pancreas. PP is a hormone secreted from the cells of Langerhans' islets in response to diet, known as a satiety factor, and reduces food ingestion and body weight gain. Ghrelin is known to stimulate food ingestion, and increase body weight gain by reducing fat oxidation.
Diabetes is a disease developed by insufficient insulin and loss of the function thereof, and difficult to cure once it is developed. Diabetes can be largely classified into two types of type I diabetes mellitus (insulin dependent diabetes) and type II diabetes mellitus (non-insulin dependent diabetes).
Type II diabetes mellitus is a chronic disease developed by resistance to insulin, which becomes problems in relation to lifestyle habits such as obesity due to overeating and inactivity, stress etc. Type II diabetes mellitus is often developed in middle-aged adults, and many of the diabetes patients are affected with type II diabetes.
Type I diabetes mellitus is a chronic disease caused by destruction of pancreatic β cells (sometimes referred to as insulin-producing cells in the present specification) by autoimmune diseases, virus infection and the like to terminate secretion of insulin in the body. As a treatment method that can automatically control blood glucose level that continuously changes in the body and reduce burden on patients, pancreas transplantation or pancreatic islet transplantation is performed on patients with type I diabetes mellitus. While it is possible to achieve a normal blood glucose level by these treatment methods, the transplantation technique has not been sufficiently established, and the pancreas and pancreatic islet that can be transplanted are not sufficient. Moreover, to avoid immune rejection to a graft, the patients need to take an immunosuppressant for the entire life, and the problems of the risk of infection, side effects caused by immunosuppressant and the like still remain.
One of the treatment methods tried for type I diabetes mellitus is a method inducing insulin-producing cells itself in vitro from cells derived from a patient, and transplanting the induced insulin-producing cells into the body of the patient. According to this method, insulin can be produced in the body of the patient. When insulin-producing cells are induced from cells derived from a patient, it is advantageous from the aspect of safety. Since the cells are derived from the patient, the problem of immune rejection etc. can be resolved.
Known methods for obtaining insulin-producing cells include a method of differentiating embryonic stem cells (sometimes to be referred to ES cells in the present specification), a method of differentiating induced pluripotent stem cells (sometimes referred to iPS cells in the present specification), a method of differentiating tissue stem cells of the pancreas of a patient, a method of extracting cells derived from the pancreatic duct epithelium of a patient in vitro and differentiating the same and the like. Specifically, a method of inducing differentiation of pancreatic β cells from human ES cells by using activin and retinoic acid (RA) (patent document 1, non-patent documents 1-4), a method of inducing differentiation of pancreatic β cells from human iPS cells (non-patent document 5), a method of efficiently inducing differentiation of insulin-producing cells, including introducing PDX1, which is known to be an important transcription factor involved in the development of the pancreas and also responsible for the development and function maintenance of insulin-producing cells, into ES cells, and cultivating the cells (patent documents 2-3), and a method including dedifferentiating hormone non-producing pancreatic cells to give stem cells, and inducing differentiation of the stem cells by using activin and RA (patent document 4).
However, since the insulin-producing cells obtained by these methods show considerably low insulin production efficiency as compared to those of normal pancreatic β cells, the development of a method of efficiently obtaining functional insulin-producing cells is still demanded. In addition, to perform treatment of diabetes and the like, the development of a method of obtaining a sufficient number of pancreatic hormone-producing cells (including insulin-producing cells) is demanded.